PROJECT SUMMARY Schizophrenia (SCZ) genomics has achieved unprecedented advances. A decade ago, there was perhaps one solid finding, and there are now 130+ loci that meet consensus criteria for significance and replication. The Swedish SCZ Study (S3) and its investigators have were centrally important to these advances. Genetic analyses of S3samples have been major parts of part of multiple high profile papers. We cooperate well with other groups, and are leaders in the PGC. There is more to do. Thus, this is a competitive renewal for the S3 project. The S3 is arguably the largest and bestcharacterized SCZ sample anywhere: we propose to make it larger and more informative. In each prior R01, we accomplished far more than we proposed. We now propose aims designed to maximize the informativeness of S3 by doubling its size, adding cognitive phenotypes, and innovative analyses. Critically, this work is multifunded and maximizes contributions from others and minimizes NIH budgetary requests. Specific Aims (1) Augment S3 dataset by doubling the sample size, add new Swedish register linkages, impute to a Swedenspecific references, and add cognitive phenotypes. Output: a large and comprehensive dataset ready for analysis. (2) Analysis: increase knowledge of the genetic basis of SCZ. Integrate data from Aim 1 with all other world samples to discover compellingly associated loci. Output: SCZ associations across the allelic spectrum. (3) Analysis: ?multiomic? integration. Combine, annotate, and rigorously evaluate results from Aim 2 with all available epigenomic, gene expression, and proteinprotein interaction data (e.g., CommonMind, psychENCODE, and SUN). Includes resequencing data of GWA loci. Output: specific hypotheses about the immediate biological impact of genetic variation implicated in SCZ. (4) Analysis: ?new epidemiology?. Combine measured genetic and environmental risk factors to evaluate independent and interactive effects on risk for SCZ. Output: knowledge about how genes and environment mediate risk for SCZ. Successful completion of this work ? capitalizing on cuttingedge technologies and a highly productive decade long collaboration ? is highly likely to advance knowledge of SCZ by identifying more loci, providing specific biological hypotheses, and understanding of GxE action and interaction. Identification of patients at risk for mortality would have immediate clinical utility. This study is preclinical. Although not proposed here due to complexity and expense, we will immediate prioritize any potential therapeutic target via collaborations (e.g., with Dr Sullivan?s UNC colleague and antipsychotic expert Dr Bryan Roth). The work proposed is highly efficient / costeffective due to our multifunding model. We have minimized costs (while maximizing the science we can achieve) via multiple strategic partnerships. We use consultancies to bring wellfunded investigators into S3. We routinely use multiple technologies to enhance collaboration.